Obesity is associated with respiratory depression that is often exacerbated by sleep. In this proposal we investigate the role of two key metabolic hormones associated with obesity in stimulating respiratory control centers. We present preliminary data that the absence of both leptin and insulin are associated with respiratory depression. Our general hypothesis is that obesity and diabetes result in progressive defects in ventilatory control that lead to hypoventilation, particularly during sleep. To examine this hypothesis we will utilize: 1) a murine model of streptozotocin (Stz)-induced insulin dependent diabetes, and 2) a murine model of obesity in leptin deficient ob/ob mice. In Specific Aim 1 we will examine the relationship between Stz-induced diabetes and decreases in plasma insulin and leptin. In Specific Aim 2 we will determine if the absence of insulin and leptin in diabetic wild type mice causes respiratory depression. In Specific Aim 3 we will determine if the replacement of insulin in diabetic ob/ob and wild type mice can reverse respiratory depression. Thus, this study will examine mechanisms by which obesity and diabetes produce respiratory depression and may lead to new therapeutic strategies for sleep disordered breathing.